Efficacy of pulse oximetry for early diagnosis of pulmonary embolism after total knee arthroplasty

Introduction Early diagnosis and aggressive treatment of pulmonary embolism (PE) are crucial for preventing severe complications after total knee arthroplasty (TKA). This study aimed to examine the efficacy of measuring oxygen saturation (SpO2) using a pulse oximeter for early diagnosis of PE after total knee arthroplasty (TKA). Materials and methods We consecutively examined 1645 patients who underwent TKA between January 2015 and November 2019. Postoperative SpO2 was measured with a pulse oximeter, which was stopped if SpO2 was maintained at ≥ 95% until postoperative day 2 (POD2). To diagnose PE, computed tomographic pulmonary angiography (CTPA) was performed for specific indications, including persistently low SpO2 < 95% (group 1), sudden decrease in SpO2 (group 2), and decrease in SpO2 after POD3 with presenting symptoms (group 3). Also, we divided the patients into unilateral, simultaneous and sequential TKA groups and compared the results with specific statistical techniques. Results Of the 1645 patients who underwent TKA, there were 20 patients with PE (1.2%), and symptomatic PE was observed in only 4 patients (0.24%). CTPA was performed in 58 (3.5%) patients, of whom 20 were diagnosed with PE. In groups 1 (n = 34), 2 (n = 21), and 3 (n = 3), CTPA was performed 2.4, 2.6, and 8.3 days after TKA, respectively, and 12, 8, and 0 patients were diagnosed with PE, respectively. Of the 782, 416, and 447 unilateral, simultaneous, and sequential (done in same admission with interval 1 or 2 weeks) patients with TKA, 38, 18, and 2 received CTPA, and 13, 6, and 1 were diagnosed with PE, respectively. All patients diagnosed with PE have persistently low SpO2 < 95% (group 1), or sudden decrease in SpO2 (group 2) until POD2. Of the patients diagnosed with PE, SpO2 decreased without the presentation of symptoms in 16 patients (11 and 5 from groups 1 and 2, respectively) and with the presentation of symptoms, such as mild dyspnea and chest discomfort, in 4 patients (1 and 3 from groups 1 and 2, respectively). Conclusions Measuring SpO2 using a pulse oximeter until POD2 was an effective method for early diagnosis of PE after TKA. No case of morbidity or mortality was observed after early diagnosis with early stage CTPA and management of PE. We recommend measuring SpO2 with a pulse oximeter for early diagnosing of PE in TKA.


Background
Postoperative venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is one of the most severe complications after total knee arthroplasty (TKA) [1].In patients who received TKA without thromboprophylaxis, the incidence of PE is reported to be approximately 1.5-10% [2,3].Symptomatic PE occurred in 0.41% of 222,684 TKA cases [4].Moreover, according to a meta-analysis of 18 studies [5], the proportion of patients with symptomatic PE was 0.37% (0.24-0.52%); the proportion was not reduced despite prophylactic anticoagulative measures due to genetic factors.The fatality rate due to PE is estimated to be 7-11% [6][7][8].Furthermore, the mortality due to PE after TKA is reported to be 0.07-0.3%when thromboprophylaxis is performed [9,10].The inpatient mortality in patients without PE is 0.1%, and with PE is 3.36%; thus, higher mortality is reported in patients with PE [11].
Accordingly, early diagnosis and aggressive treatment of PE are crucial for preventing severe complications regardless of the presenting symptoms [6,8,10].PE is diagnosed using one or more tools: plasma d-dimer levels, computed tomographic pulmonary angiography (CTPA), ventilation-perfusion scintigraphy, pulmonary angiography, magnetic resonance angiography, and echocardiography [3,5,[7][8][9].PE has various presenting features ranging from no symptoms to death; thus, the same diagnostic tools cannot be applied to all patients [6,10].When pulmonary artery occlusion occurs due to acute PE, blood flow is redistributed to the nonoccluded vessels.It causes ventilation/perfusion (V/Q) mismatch, which leads to inadequate gas exchange, hypoxemia, and hypocapnia [2,5,[8][9][10].Patients can present various clinical symptoms such as dyspnea, tachypnea, chest pain, and so on.In addition, hypoxemia is present in about 74% of patients with acute PE on initial blood gas analysis.Thus, persistent hypoxemia after surgery indicates the possibility of PE.
A non-invasive and convenient method for detecting hypoxemia is a pulse oximeter.In this study, all patients in postoperative care were monitored for hypoxemia using a pulse oximeter.Regardless of the presenting symptoms, patients with a persistent or sudden decrease in oxygen saturation (SpO 2 ) underwent CTPA.In the patients diagnosed with PE, the management and prognosis were evaluated.Therefore, this study aimed to examine the efficacy of measuring oxygen saturation (SpO 2 ) using a pulse oximeter for early diagnosis of PE in TKA.
The hypothesis was that measuring SpO 2 with a pulse oximeter after TKA is an effective and convenient method for the early diagnosis of PE.

Methods
This study consecutively examined 1645 [782 unilateral, 416 simultaneous, and 447 sequential (done in the same admission with the interval of 1-2 weeks)] patients who underwent TKA by a single surgeon between January 2015 and November 2019.This study was a retrospective cohort study approved by the Institutional Review Board.
SpO 2 was measured with a pulse oximeter in all patients until the postoperative day 2 (POD2).Postoperative SpO 2 was measured using a pulse oximeter (Nonin Onyx Vantage 9590).NexGen Legacy Posterior Stabilized Flex Fixed Bearing (LPS Flex Fixed, Zimmer Warsaw, IN, USA) was used, and the mini-midvastus approach with minimally invasive surgery using quad-sparing ™ instrumentation was utilized to perform TKA.We performed simultaneous TKA if a patient did not have comorbidities (such as coronary artery disease, chronic heart failure, chronic renal failure or stroke, etc.) or was under the age of 75 years.On the other hand, if a patient had comorbidities or was over the age of 75 years, we performed sequential TKA, and also sequential TKA was performed in the same admission with intervals of 1 or 2 weeks.Patients were hospitalized for up to 2 weeks after surgery for postoperative care, and postoperative rehabilitation begins on POD1 or 2 with a continuous passive motion (CPM) device or self-range of motion (ROM) exercise.
Pulse oximetry monitoring was started immediately when a patient returned to the ward with the 24-h monitoring device and then stopped if SpO 2 was maintained at ≥ 95% without presenting symptoms of PE.On the other hand, regardless of the presenting symptoms, CTPA was performed for specific indications, including persistently low SpO 2 < 95% (group 1), sudden decrease in SpO2 (group 2), and decrease in SpO 2 after POD3 with presenting symptoms (group 3).Patients who received CTPA were categorized into two groups: PE diagnosed (group A) and non-diagnosed (group B) (Table 1) with a radiographic reading and confirmation of CTPA result from the department of radiology and specific laboratory studies.
Routine protocol was that a fondaparinux injection dose of 2.5 mg with subcutaneous injection from POD3 to POD7 to prevent venous thromboembolism was administered to all patients.

Statistical analysis
Pearson's chi-squared test was used to analyze the nominal variables.The independent t-test was used to compare continuous variables and determine statistical significance, the chi-squared test was performed for categorical variables, and weighted kappa coefficients were calculated.SPSS was used for statistical analysis, and the results were statistically significant at a p < 0.05.

Results
Of the 1645 patients who underwent TKA, there were 20 patients with PE (1.2%) and symptomatic PE was observed in only 4 patients (0.24%).CTPA was performed in 58 (3.5%) patients, of whom 20 (34.5%) were diagnosed with PE (Table 1).Of the patients who received CTPA, no significant difference was found between group A (PE diagnosed) and group B (nondiagnosed) regarding age, sex, body mass index (BMI), surgery site, comorbidities (hypertension, diabetes, ischemic heart disease, and old cerebrovascular disease), the timing of CTPA, and clinical manifestations (Table 1).
Of the 782 patients who underwent unilateral TKA, 38 received CTPA and 13 (34.2%)were diagnosed with PE.Of the 416 patients who underwent simultaneous TKA, 18 received CTPA and 6 (33.3%) were diagnosed with PE.Of the 447 patients who underwent sequential TKA, two received CTPA and 1 (50%) was diagnosed with PE.Of the patients diagnosed with PE, SpO 2 was decreased without presenting symptoms in 16 patients (11 from group 1 and 5 from group 2).And there were four patient presenting with symptoms such as mild dyspnea and chest discomfort (one from group 1 and three from group 2) (Table 3).In this study, segmental PE was most frequently observed; there were 11 cases of segmental PE, 7 of subsegmental PE, and 2 of lobar PE.
As for the management of PE, it is important to decide first-line drug and when to start using the drug.Because it must be decided in consideration of various conditions, such as the patient's underlying disease, it is important to have close consultation with internal medicine department.Four patients received unfractionated heparin (UFH) for 2-5 days (3 days on an average) followed by non-vitamin K antagonist oral anticoagulant (NOAC) for 1 day or until 32 weeks (27.3 weeks) (Table 4).Six patients received fondaparinux [low molecular weight heparin (LMWH)] for 2-10 days (5 days on average) followed by NOAC for 2-72 weeks (29.5 weeks).One patient received only LMWH for 13 days, and nine received only NOAC for 16-66 weeks (29.6 weeks) (Fig. 1).Medical treatment was stopped in one patient who received UFH for 3 days, followed by NOAC for 1 day due to severe hemorrhage and edema of the left leg.This patient underwent arthrocentesis and elastic band fixation; moreover, aspirin was administered 3 weeks after surgery when the patient was discharged without signs of bleeding.All patients were observed for at least 6 months after treatment.No case of morbidity or mortality was observed.Due to nonspecific and unreliable symptoms, signs, and laboratory evidence, an early diagnosis of PE remains difficult [12][13][14].Failure of early diagnosis may lead to more severe clinical features, such as hemodynamic instability, right ventricular dysfunction, hypotension, obstructive shock, and obstructive shock, eventually causing death [15,16].Thus, early diagnosis and management of asymptomatic and mild PE can significantly reduce serious postoperative complications including death.
According to Watanabe et al., measuring postoperative d-dimer and cross-linked fibrin degradation products by leukocyte elastase (e-XDP) is helpful in predicting and diagnosing early postoperative VTE and PE [17].d-dimer is the degradation product of cross-linked fibrin blood clots that increase in plasma when both coagulation and fibrinolysis are activated due to acute thrombosis [18].e-XDP is a fibrin degradation product that is degraded by leukocyte elastase secreted by activated leukocytes and is useful in diagnosing disseminated intravascular coagulation and DVT [19,20].Watanabe et al. explained that the increase in POD1 e-XDP and POD4 d-dimer could be used for the early diagnosis of symptomatic VTE in patients with DVT after undergoing TKA.However, d-dimer levels can also be increased by any recent major surgery, hemorrhage, trauma, malignancy, and sepsis; thus, d-dimer levels cannot be used as a stand-alone diagnostic test for VTE [21].On the other hand, the negative predictive values of d-dimer and e-XDP are above 98%; therefore, they are still useful as screening tests to exclude VTE.Thus, given that d-dimer and e-XDP are within normal plasma levels, no additional diagnosis examination is required [18][19][20][21].Uchiyama et al. [22].reported that dielectric blood coagulometry could help predict the occurrence of VTE after TKA.A platelet activation-dependent antigen, P-selectin, present on the platelet surface when platelets are activated by venous thrombosis, could also be an early marker for VTE [23].
When PE occurs, thrombosis in the pulmonary vasculature and outflow tract causes impaired blood flow and increased pulmonary artery pressure.This induces the secretion of humoral mediators, such as serotonin and thromboxane A2, from the platelets into the thrombus  leading to vasoconstriction and an increase in pulmonary vascular resistance.Eventually, a V/Q mismatch causes hypoxemia [13,[24][25][26].The presence of postoperative hypoxemia indicates the possible occurrence of PE; thus, an appropriate evaluation of hypoxemia may help diagnose early PE.SpO 2 measured by a pulse oximeter allows for the non-invasive measurement of arterial oxygen saturation (SaO 2 ), which helps evaluate hypoxemia in various circumstances [27].In 2004, a study suggested eight PE rule-out criteria, including SpO 2 > 94%, to reduce the excessive d-dimer measurements as the screening test for diagnosing possible PE [28].In addition, SpO 2 is included in the 11 evaluation criteria of the Pulmonary Embolism Severity Index suggested by Aujesky et al. [29].
A discrepancy between SpO 2 measured using a pulse oximeter and actual SaO 2 is inevitable.According to Wilson et al. [30], SpO 2 -SaO 2 is 2.75% ± 3.1%; thus, the measured value of SpO 2 is higher than that of SaO 2 .A total of 50% of the patients with 90-93% SpO 2 had hypoxemia (SaO 2 ≤ 90%); thus, using a pulse oximeter may lead to an underestimated diagnosis of hypoxemia [26,30].Therefore, a criterion for appropriately evaluating hypoxemia is required for a pulse oximeter.According to the retrospective evaluation of patients in the intensive care unit [14,30], the cutoff value of SpO 2 to detect hypoxemia (SaO 2 ≤ 90%) was 94%.And the in-hospital morbidity rate due to PE was significantly reduced when SpO 2 was ≥ 95% [23].In addition, 95% SpO 2 , measured by a pulse oximeter, is the sole criterion to classify patients with PE into high-and low-risk groups [27,29,30].Measurement errors may occur depending on the type of pulse oximeter; however, regardless of the measuring device, persistent SpO 2 in the range of 95-100% confirms that a patient is not hypoxic [30].
Therefore, SpO2 ≥ 95% was used in this study to confirm that the patient did not have hypoxemia.A total of 58% of patients with SpO 2 < 95% received CTPA, considering the possibility of hypoxemia due to PE.Of these patients, 20 (34.5%) were diagnosed early with PE.Of the 20 patients diagnosed with PE, 16 showed no symptoms and only 4 had mild dyspnea and chest discomfort, which are not typical clinical features of PE.Thus, utilization of SpO 2 is clinically meaningful as a screening test for PE in patients who are either asymptomatic or present with mild symptoms.
In this study, if a patient takes medications such as anticoagulants or antiplatelet drugs, we stopped the drug some days before with delicate collaboration with internal medicine or neurology departments.After that LMWH (fondaparinux) was administered to all patients in POD3 to POD7 to prevent VTE.Either UFH followed by NOAC or NOAC alone was administered to patients diagnosed with PE before POD3.When PE was diagnosed during the administration of LMWH, LMWH was continued for some time before changing to NOAC.As for the management of PE, four patients received UFH for 2-5 days (3 days on average) followed by NOAC for 1 day to 32 weeks (27.3 weeks), six patients received LMWH (fondaparinux) for 2-10 days (5 days on an average) followed by NOAC for 2-72 weeks (29.5 weeks), one patient received only LMWH for 13 days, and nine patients received only NOAC for 16-66 weeks (29.6 weeks).Medical treatment was stopped in a patient who received UFH for 3 days, followed by NOAC for 1 day, due to severe hemorrhage and edema of the left leg.This patient underwent arthrocentesis and elastic band fixation; moreover, aspirin was administered 3 weeks after surgery when the patient was discharged without signs of bleeding.
Even though PE may also be asymptomatic and need any other treatment, some PE may become symptomatic and even cause death.Dentali et al. reported on their meta-analysis study; overall weighted mean prevalence of incidental PE was 2.6%, and the prevalence rose in high-risk patients who had cancer, DVT, and so on.In addition, results of some study showed high mortality rate of asymptomatic PE.Anja Boc et al. reported a study of the relationship between deep vein thrombosis and asymptomatic PE.In their study, about 36.1% of patients with DVT were related with asymptomatic PE and asymptomatic PE was one of the risk factors of recurrent PE.Trozan et al. reported 40% of recurrent PE was fatal.So, we need to check the PE with a noninvasive modality for detecting PE, if possible.This study shows we can detect PE early using non-invasive modalities such as pulse oximetry.
There are some limitations to this study.First, the limitation of this study is that the study period (2015-2019) is relatively short, and there are characteristics of the disease that require long-term follow-up, and so it has the disadvantage that it does not reflect the overall natural history of the disease.Also, there is a limitation that other causes that may affect the PE and condition, such as underlying comorbidities, deep vein thrombosis and methods of prophlactics, opioid use, or age etc., could not be observed or analyzed.We did not check the Doppler sonography for detecting DVT.Also we did not check all patients' SaO 2 , and it might underestimate some patients according to Wilson et al.
This study's conclusions were drawn given that it is a sample only of a single surgeon's patients with TKA.
Patients diagnosed with PE can easily be overlooked due to the presentation of atypical symptoms.

Conclusions
Measuring SpO 2 with a pulse oximeter is clinically meaningful to determine PE after TKA.In addition, there was no morbidity or mortality case after early diagnosis with early stage CTPA and management of PE.In conclusion, measuring SpO 2 with a pulse oximeter after TKA is an effective and convenient method for the early diagnosis of PE.

Fig. 1 a
Fig. 1 a 66-year-old female patient complained of dyspnea and showed SpO 2 90% on POD2 after both TKA.Pulmonary thromboembolism (PTE) in right lower lobe lobar artery was detected.b LMWH was administrated for 5 days followed by Pradaxa for 15 weeks.Pulmonary embolism disappeared after medication

Table 1
Patient demographics and clinical data Data are presented as means with standard deviation (p < 0.05) CVA cerebrovascular accident, CTPA computed tomographic pulmonary angiography, PE pulmonary embolism

Table 3
Twenty cases of pulmonary embolism Location of embolism: segmental artery (11 cases), subsegmental artery (7 cases), lobar artery (2 cases) p = 0.255 of PE.In this study, there were 20 patients with PE (1.2%) and symptomatic PE in only 4 patients (0.24%) of the 1645 patients who underwent TKA.Early diagnosis and management of PE are crucial as PE after TKA can cause serious complications including death.

Table 4
Management of pulmonary embolism